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Saito et al. World Journal of Surgical Oncology 201 3, 1 1 :202 
http://www.wjso.eom/content/1 1 /I /202 



WORLD JOURNAL OF 
SURGICAL ONCOLOGY 



RESEARCH Open Access 



Histopathological and clinical characteristics of 
duodenal gastrointestinal stromal tumors as 
predictors of malignancy 

Tsunenori Saito 1 ' 2 * Masaki Ueno 2 , Yasunori Ota 3 , Yoshiharu Nakamura 4 , Masaji Hashimoto 2 , Harushi Udagawa 2 , 
Kyoichi Mizuno 1 , Kenichi Ohashi 5 and Goro Watanabe 2 



Abstract 

Background: Although gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the 
gastrointestinal tract, they are very rare. This study evaluated clinical and histopathological characteristics of 
duodenal GISTs to identify factors useful in predicting prognosis for patients with these tumors. 

Methods: A retrospective study was performed on 20 patients who had undergone surgery between 1987 and 
2009 for duodenal GISTs. Clinical, histopathological, and immunohistochemical data were evaluated. Survival 
analyses were conducted using Kaplan-Meier estimates. 

Results: In 12 patients (60%), duodenal GISTs were diagnosed incidentally. Eight cases (40%) were classified as high 
risk grade GISTs. Skeinoid fibers (SkF), which are eosinophilic globular hyaline deposits in the extracellular 
interstitium of the tumor, were found in 12 patients. Skeinoid fibers were not recognized in 8 cases, and these 
included 3 cases (37.5%) where tumors recurred after surgery and the patient died. Tumors without SkF were larger 
(81 ±92 vs. 23 ±8 mm, P < 0.001) and had a higher mitotic count (224.0 ±336.6 vs. 0.0 ±0.0 /50 high-power 
field, P < 0.001) than those with SkF. Survival time was shorter in patients with tumors lacking SkF (52.9 ± 50.7 vs. 
1 08.9 ± 86.5 months, P = 0.01 9). 

Conclusions: We have identified clinical and histopathological characteristics that were useful in predicting the 
prognosis of patients with duodenal GISTs. In this study, 60% of the tumors were found incidentally, SkF were not 
recognized in tumors from 40% of patients, and all cases of post-operative tumor recurrence and death occurred in 
this subgroup of patients. 

Keywords: Duodenal GIST, Skeinoid fiber, Histopathology, Prognosis, Medical examination 



Background 

Gastrointestinal stromal tumors (GISTs) are the most 
common mesenchymal tumors affecting the gastrointes- 
tinal tract [1]. The cells in these tumors show differenti- 
ation toward the interstitial cells of Cajal [2]. The majority 
of GISTs express a growth factor receptor with tyrosine 
kinase activity termed KIT which is constitutively activated. 
KIT is the product of the proto-oncogene CD 117 (c-kit) 
[3]. In GISTs, morphologic features including mitotic 



* Correspondence: tnsaitonms@gmail.com 

department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, 
Bunkyo-ku, Tokyo 1 13-8603, Japan 

department of Digestive Surgery, Toranomon Hospital, 2-2-2 Toranomon, 
Minato-ku, Tokyo 105-0001, Japan 

Full list of author information is available at the end of the article 



count and tumor size have been most acknowledged to 
be important in predicting malignant tumor behavior 
[4]. These tumors are common in the stomach (60-70% 
of cases) and small intestine (30%). However, duodenal 
GISTs are very rare and constitute less than 5% of all 
GISTs [5] . There are very few reports describing duodenal 
GISTs [6-9]. 

Duodenal and intestinal GISTs contain skeinoid fibers 
(SkF); eosinophilic globular hyaline deposits found in the 
extracellular interstitium of the tumor. The ultrastruc- 
tural appearance of SkF is similar to that of the skein of 
yarn [10]; however the composition and origin of SkF re- 
mains unknown. Several studies [4-7,10,11] suggest that 
SkF in GISTs are associated with low tumor proliferative 



© 2013 Saito et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative 
BiolVlGCl C6ntTcll Commons Attribution License (http://creativecommons.Org/licenses/by/2.0), which permits unrestricted use, distribution, and 
reproduction in any medium, provided the original work is properly cited. 



Saito et al. World Journal of Surgical Oncology 201 3, 1 1 :202 
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Page 2 of 7 



activity, but the association between SkF in duodenal 
GISTs, tumor malignancy and patient prognosis has not 
been investigated thoroughly. 

The aim of this study was to evaluate the clinical and 
histopathological characteristics of duodenal GISTs, to 
determine factors useful in predicting patient prognosis. 

Methods 

Clinical background 

A retrospective study was performed using clinical and 
pathological data from 20 patients with duodenal GISTs. 
Patients who underwent surgery for duodenal GISTs 
between November 1987 and May 2009 were enrolled 
in the study; 12 had undergone surgery in Toranomon 
Hospital and 8 in Nippon Medical School Hospital. 
The diagnosis of GIST was confirmed after pathological 
review and positive immunoreactivity for KIT. The 

Table 1 Characteristics of patients with duodenal GISTs 



diagnosis of GIST was also confirmed in KIT negative tu- 
mors based on morphology and positive CD34 immuno- 
histochemical results. Confirmatory mutation studies were 
not performed. The study population comprised 9 men 
and 11 women; aged 42 to 79 years (mean 60 ± 12 years). 
All patients gave written informed consent within an ap- 
proved ethics process. The study was conducted in accord- 
ance with the Declaration of Helsinki.Clinical background, 
including age, sex, chief complaint, method of GIST detec- 
tion, location of GIST in the duodenum, and surgical pro- 
cedures used are detailed in Table 1. 

Histopathological assessment 

The gross features of the duodenal GISTs, including 
growth pattern and tumor size, were verified from surgical 
and pathological records. Tumor tissue samples were fixed 
in 20% neutral buffered formalin, embedded in paraffin, 



Variable 



Total 



SkF group 



non-SkF group 



P value 



Number 20 12 

Age - yr (mean ± SD) 59.9 ±11.6 63.6 ±9.8 

Male/Female sex - no. (% male) 9/1 1 (45) 2/1 0 (1 6.7) 

Presentation reason - no. (%) 

Medical check-up 1 0 (50%) 6 (50%) 

Bleeding 3(15%) 2(17%) 

Anemia 5(25%) 2(17%) 

Others* 2(10%) 2(17%) 

Diagnostic method - no. (%) 

Fiber-optic gastroscopy 14 (70%) 7 (58%) 

Abdominal ultrasonography 2(10%) 1(8%) 

Upper gastrography 2 (1 0%) 2 (1 7%) 

Abdominal computed tomography 1 (5%) 1 (8%) 

Operation for another gastrointestinal disease 1 (5%) 1 (8%) 

Therapeutic surgical procedure - no. (%) 

Partial resection 1 7 (85%) 12(1 00%) 

Distal gastrectomy 2(10%) 0(0%) 

Pancreaticoduodenectomy 1 (5%) 0 (0%) 

Site of tumor in duodenum - no. (%) 

1 st portion of the duodenum 5 (25%) 4 (33%) 

2nd portion of the duodenum 9 (45%) 5 (42%) 

3rd portion of the duodenum 4 (20%) 2 (1 7%) 

4th portion of the duodenum 2 (10%) 1 (8%) 

Risk of aggressive tumor behavior (modified AFIP consensus criteria) 12 - no. (%) 

Very low risk 3 3 

Low risk 9 9 

High risk 8 0 



54.3 ±12.3 
7/1 (87.5) 

4 (50%) 
1 (13%) 
3 (38%) 
0 (0%) 



7 ( 

1 (13%) 
0 (0%) 
0 (0%) 

0 (0%) 

5 (63%) 

2 (25%) 

1 (13%) 

1 (13%) 
4 (50%) 

2 (25%) 
1 (13%) 

0 
0 



0.048 
0.003 

0.675 
0.656 
0.296 
0.347 

0.187 
0.653 
0.347 
0.600 
0.600 

0.049 
0.147 
0.400 

0.307 
0.535 
0.535 
0.653 

0.193 
0.001 
<0.001 



Data expressed as mean ± SD, where appropriate. AFIP = Armed Forces Institute of Pathology. 

* One patient's duodenal GIST was detected when she had a gastric smooth muscle tumor resected, and another patient's duodenal GIST was detected i 
incidental finding on a computed tomographic scan of the abdomen performed to screen for metastasis of malignant melanoma. 



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and sectioned at a thickness of 3 (im. Serial sections were 
stained with hematoxylin and eosin, Elastica van Gieson 
(EVG) or Elastica-Masson Goldner (EMG), periodic acid 
and Schiff (PAS) stain, and diastase treated PAS stain. 
Three authors (T.S., Y.O., and ICO.) assessed each sample 
for histologic and immunohistochemical evidence of GIST. 
We examined the specimens 3 times in random order, with 
the pathologist blinded to the clinical background of the 
individuals from whom the tumors were removed. Histo- 
pathologic evaluations were determined by consensus in 
the case of inter-pathologist differences. The following 
histological findings were recorded for each tumor: ulcer- 
ation of the tumor surface; tumor necrosis; shape of tumor 
cell (spindled cell pattern, epithelioid cell pattern, and 
mixed spindle and epithelioid cell pattern); nuclear shape 
and enlargement; total number of mitoses in 50 high- 
power fields (HPF; x40 objective and x 10 ocular lenses), 
and presence of SkF, on an Olympus BX-50 microscope 
(Olympus Optical Co., Tokyo, Japan). 

Immunohistochemistry 

Indirect immunoperoxidase staining, with or without 
heat-induced epitope retrieval (autoclaving for 5 min in 
10 mmol/L citrate buffer, pH 6.0), was performed using 
consecutive silane-coated paraffin sections sampled from 
the tumor-nontumor junction. The target differentiation 
antigens, visualized using monoclonal and polyclonal 
antibodies, included smooth muscle markers such as 
a-smooth muscle actin (SMA) and desmin, and Schwann 
cell-related markers such as S-100 protein. Immuno- 
staining was used to detect KIT and CD34. To demon- 
strate proliferative activity, paraffin-resistant Ki-67 antigen 
was detected immunohostochemically by heating paraffin- 
embedded tumor tissue and then staining with MIB-1 anti- 
body. The results were evaluated using the following 
criteria: negative, focally positive (less than 50% of tumor 
cells showing a positive reaction); diffusely positive (more 
than 50% of tumor cells stained). The labeling indices of 
MIB-1 antibody were evaluated by counting positive nuclei 
in 1000 tumor cells. 

Classification of aggressive behavior in duodenal GISTs 

The malignant potential of the tumors was estimated based 
on tumor size and mitotic count, according to the modified 
Armed Forces Institute of Pathology (AFIP) consensus cri- 
teria for risk stratification of duodenal GISTs [12]. 

Statistical analysis 

The discontinuous variables, such as observational histo- 
pathological results and patient numbers for some clinical 
parameters, were compared by Fisher s exact method. The 
continuous variables, such as clinical data, were eval- 
uated by Wilcoxon rank-sum test. Disease free survival 
and overall survival were calculated using the Kaplan- 



Meier method. Univariate analysis was performed using 
the Log-rank test. Statistical analyses were performed 
using the SPSS software package (SPSS Inc., Chicago, 
IL, USA). All data were expressed as the mean ± SD. 
P values < 0.05 were considered significant. 

Results 

Clinical findings, tumor location, and surgery 

The baseline clinical characteristics of patients with duo- 
denal GISTs are summarized in Table 1. Gastrointestinal 
hemorrhage, manifested by hematemesis or melena, was 
the most frequent symptom. Ten (50%) of patients were 
asymptomatic and incidentally detected during physical 
examination for investigation of another disease. In 2 
patients, the tumor was incidentally detected during a 
medical procedure or abdominal surgery performed for 
another reason. In the first patient the duodenal GIST 
was detected during resection of a gastric smooth muscle 
tumor, and in the second patient the duodenal tumor was 
identified in a computed tomographic scan of the abdomen 
performed to screen for metastatic malignant melanoma. 

Of the 20 duodenal GISTs, 5 were in the 1st portion 
of the duodenum, 9 in 2nd portion, 4 in 3rd portion, 
and 2 in 4th portion. Fourteen patients were treated with 
segmental duodenal resection, 3 cases had tumor resec- 
tion, 2 cases had distal gastrectomy, and 1 patient had 
pancreatoduodenectomy. Two patients who had distal 
gastrectomy performed, had GISTs located in the 1st 
portion of the duodenum. One of these two cases had a 
complicated smooth muscle tumor in the pyloric part 
of stomach. There were no cases of acute abdomen 
prompting emergency surgery. There were also no neuro- 
fibromatosis type 1 patients with small intestinal GISTs. 
A patient, with a 32 mm diameter duodenal GIST, received 
400 mg per day of Imatinib (STI571, Gleevec®) preopera- 
tively for 2 months, but as there was no apparent effect on 
the tumor, tumor resection was performed. 

Histopathological and immunohistochemical findings 

Mean tumor size was 32 ± 27 mm. Ulceration was recog- 
nized in 15 cases, and coagulation necrosis of the tumor 
was seen in 6 cases. Twelve cases were classified as hav- 
ing a spindle cell pattern, 7 cases had an epithelioid cell 
pattern, and one case had a mixed spindle and epithelioid 
cell pattern. Nuclear pleomorphism was usually moderate. 
The mitotic count in the 20 duodenal GISTs ranged from 
less than 1 to 934 mitotic figures 150 HPFs (mean: 89.6 ± 
233 /50 HPFs). The mitotic count was <5 /50 HPFs in 
14 cases (70%), and 4 tumors (20%) had more than 50 
mitosis /50 HPFs. All 20 cases had documented KIT 
positivity. Two cases showed KIT positivity in less than 
30% of the tumor cells. CD34 reactivity was seen in 14 
cases (70%), S-100 was positive in 14 cases (70%), a-SMA 
was reactive in 14 cases (70%), and 11 cases (65%) were 



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positive for desmin. These immunohistochemical findings 
were not found to be significantly associated with malig- 
nant behavior in duodenal GISTs or patient prognosis. All 
GISTs had positive reactivity for MIB-1. The MIB-1 index 
of duodenal GISTs was 1.8 ± 1.2 (range 0.15-60). 

Association of clinical factors and presence 
of skeinoid fibers 

Skeinoid fibers, which are variably sized eosinophilic 
globules, were located between tumor cells and were 
surrounded by an artifact-like empty halo (Figure 1). 
These fibers stained positively with PAS stain, and nega- 
tively with EVG and EMG stains. Their diastase treated 
test was also negative. Skeinoid fibers also showed no 
immunoreactivity with KIT, CD34, a-SMA, desmin, and 
S-100. These fibers were recognized in 12 duodenal 
GISTs (SkF group), with the other 8 tumors lacking these 
fibers (non-SkF group). Clinical differences between these 
2 groups are shown in Table 1 and pathological differ- 
ences in Table 2. The GISTs size in the non-SkF group 
was significantly larger than in the SkF group (81 ± 92 vs. 
23 ± 8 mm, P < 0.001). All tumors in the non-SkF group 
were ulcerated. Tumor necrosis was present in 6 tumors: 
all in the non-SkF group. Cellular shape (spindle or epi- 
thelioid cell pattern) had no correlation with presence of 
SkF. The mitotic count and MIB-1 index in the non-SkF 
group was also greater than that in SkF group (224.0 ± 
336.6 vs. 0.0 ± 0.0 150 HPF, P < 0.001; and 26.3 ± 20.3 vs. 
1.8 ± 1.2, P < 0.001, respectively). 

Classification of aggressive behavior in duodenal GISTs 

According to the modified AFIP consensus criteria for risk 
stratification of GISTs [12], in this study there were 3 tu- 
mors in the very low risk category, 9 in the low risk, and 8 
in the high risk. All patients with tumors in the SkF group 
were classified with either a very low or a low risk of ag- 
gressive tumor behavior, and those in the non-SkF group 
with high risk of aggressive tumor behavior Figure 2. 

Survival and tumor recurrence 

Seventeen (85%) patients were alive with no evidence of 
disease for a median survival time of 6.0 years. Overall 
tumor-specific mortality was 15% (3 of 20) in patients 
with follow-up. Of these patients, one was a woman and 
two were men. Their duodenal GISTs recurred a mean 
of 9.6 ± 5.8 months after the initial operation. One pa- 
tient had liver metastasis and two patients had abdom- 
inal metastasis. They died due to this disease a mean of 
49.9 ± 68.3 months following recurrence, all being in the 
no SkF group. We performed a combination analysis 
using the Kaplan-Meier method (Figure 3) and Log-rank 
test, both of which showed that the non-SkF group had 
a significantly shorter survival time (52.9 ± 50.7 vs. 108.9 ± 
86.5 months, P = 0.019). 




* 




Figure 1 Histopathological findings in duodenal gastrointestinal 
stromal tumors, (a) 61 year old woman without recurrence 
post-operatively. The tumor, size 33 mm, consists of spindle cells with a 
fascicular arrangement. Skeinoid fibers (SkF, *) are seen between the 
spindle cells (hematoxylin and eosin stain), (b) and (c) 61 year old 
woman without tumor recurrence post-operatively. The tumor size was 
25 mm. Periodic Acid-Schiff reactivity is positive in SkF (b) and negative 
in the diastase digestion test (c). Scale bar = 100 urn in a, b, and c. 



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Table 2 Pathological and immunohistochemical findings in duodenal GISTs, and a list of primary antibodies 
used in diagnosis 



Variable 


Dilution, Source of Antibodies 


Total 


SkF group 


non-SkF group 


P value 


Number 




20 


12 


8 




Tumor size - mm 




46.5 ± 63.4 


23.3 ± 8.2 


81.2 ±92.2 


<0.001 


Spindle type cell - no. (%) 




13 (65%) 


8 (67%) 


5 (63%) 


0.608 


Necrosis - no. (%) 




6 (30%) 


0 (0%) 


6 (75%) 


<0.001 


Ulceration - no. (%) 




15 (75%) 


7 (58%) 


8 (100%) 


0.051 


Mitosis - no. per 50 HPF 




89.6 ±233.3 


0.0 ± 0.0 


224.0 ± 336.6 


<0.001 


Mib-1 index -% 


1:200, autoclave; MBL 


1 1 .6 ± 1 7.4 


1 .8 ± 1 .2 


26.3 ± 20.3 


<0.001 


KIT - no. (%) 


1:100, autoclave; Dako 


20 (100%) 


12 (100%) 


8 (100%) 


0.999 


CD34 - no. (%) 


1 :1 00, autoclave; Ventana 


14 (70%) 


9 (75%) 


5 (63%) 


0.455 


S-100- no. (%) 


1:1000; Dako 


14 (70%) 


9 (75%) 


5 (63%) 


0.455 


a-smooth-muscle actin - no. (%) 


1:200, autoclave; Dako 


14 (70%) 


9 (75%) 


5 (63%) 


0.455 


Desmin - no. (%) 


1:40, autoclave; Dako 


1 1 (55%) 


8 (67%) 


3 (38%) 


0.205 



Data expressed as mean ± SD, where appropriate. 



Discussion 

The present study showed that duodenal GISTs, without 
any metastasis or local invasion, may be completely cured 
by early resection. In this study, 12 cases had SkF in the 
extracellular interstitium between tumor cells. In our ob- 
servation, all tumors containing SkF were of low grade ma- 
lignancy; the prognosis for patients with duodenal GISTs 
with SkF was significantly better than for those with tu- 
mors lacking SkF. 

Predicting the malignant potential of GISTs may be diffi- 
cult, and there is currently no consensus on risk estimates 



Figure 2 Histopathological features of a duodenal gastrointestinal 
stromal tumor. 44 year old man with tumor recurrence after 
resection; recurrence detected as hepatic metastasis and peritoneal 
disseminations. Tumor size was 110 mm. Tumor showing proliferation 
of spindle cells arranged in interlacing bundles. There were no skeinoid 
fibers in this tumor (hematoxylin and eosin stain). Scale bar = 00 urn. 



for metastasis to the liver or peritoneum, or for patient 
mortality. For example, small tumors with a low mitotic 
rate may still metastasize. Further, GISTs in the small 
intestine seem to behave more aggressively than gastric 
GISTs of similar size and mitotic activity [12,13]. Miettinen 
et al. [7] proposed that duodenal GISTs whose mitotic 
count exceeded 2 mitoses /50 HPFs be regarded as high 
grade malignancies. However, prominent nuclear pleo- 
morphism and hyperchromasia are rare in duodenal GISTs. 



1.0 



0.8 



0.6 



0.4 



0.2 



0.0 



SkF group 



non-SkF group 



0 50 100 150 200 250 300 

months 

Figure 3 Disease-specific survival after resection of duodenal 
GIST. Patients without skeinoid fiber (SkF, n = 8) had significantly 
worse survival than those with SkF (n = 12, P = 0.019). 



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Mortality also occurs in patients whose duodenal GISTs are 
large, even if the mitotic count is low, so that tumor size is 
the most important factor in grading malignancy of duo- 
denal GISTs. Early diagnosis and resection of duodenal 
GISTs, improves patient prognosis. 

Japanese proactively seek medical examination includ- 
ing fiber-optic gastroscopy (FGS) and abdominal ultra- 
sonography. This enables early detection of duodenal 
GISTs. In our study, 12 of 20 duodenal GISTs (60%) 
were found incidentally, and 5 of these 12 cases were 
detected endoscopically. In addition, 7 cases (35%) were 
recognized by FGS performed to investigate the cause of 
gastrointestinal bleeding or the cause of anemia. Therefore, 
12 patients (60%) had their duodenal GISTs detected by 
endoscopy. In our study, 60% of patients were at very low 
or low risk from aggressive tumor behavior according to 
modified AFIP consensus criteria for risk stratification of 
GISTs, in which the main contributor to risk is tumor size 
[12]. Gastrointestinal stromal tumors in Japanese patients 
have been reported to contain similar genetic mutations to 
GISTs in patients from other countries [14]. The early de- 
tection of GISTs allows prevention of metastasis or local 
tumor invasion and improved prognosis for patients with 
duodenal GISTs. 

The composition of SkF is still unknown. These fibers 
were present between tumor cells and were surrounded 
by an artifact-like empty halo; suggesting SkF were com- 
posed of solider elements than tumor cells. Skeinoid fibers 
appear as tangles of fibers similar to regular collagen, with 
cross-banding of 41-45 nm periodicity, and their length 
are shorter than normal collagen fibers [15]. Some studies 
reported that SkF contain type VI collagen [10,15,16]. We 
regard SkF to consist of a type of polysaccharide because 
they stain positively with PAS and negatively with the dia- 
stase digestion test (Figure lb and c). They also show 
no immunoreactivity with KIT, CD34, a-SMA, desmin, 
or S-100 immunostaining. 

In this study, all duodenal GISTs with SkF in the 
extracellular interstitium were categorized as very low or 
low risk according to the modified AFIP criteria for risk 
stratification of GISTs, and 8 cases lacking SkF were cat- 
egorized as high risk due to their size and number of mi- 
toses. These results suggest SkF are associated with less 
aggressive behavior in duodenal GISTs. We hypothesize 
that the material SkF are composed of has been secreted 
from tumor cells and retained in the extracellular space. 
Highly malignant GISTs grow rapidly, suggesting that 
secretion of the SkF material does not have time to 
accumulate in rapidly proliferating highly malignant duo- 
denal GISTs. 

Genetic research has shown that GISTs with spindle 
type cells and those with SkF contained a c-kit mutation, 
and GISTs with epithelioid type cells and those without 
SkF had an internal tandem duplication in exon 11 of 



PDGFRA mutation [17]. This led to the hypothesis that 
SkF may be a product of c-kit. However in our study, 
there was no relationship between tumor cell type and 
presence or absence of SkF, and SkF showed negative 
reactivity on KIT immunostaining. PDGFRA encodes a 
cell surface tyrosine kinase receptor for members of the 
platelet-derived growth factor family. It is located near to, 
and is structurally similar to, c-kit, leading to speculation 
of a similar origin for both genes. Therefore, this study 
suggests there may be no association between either gene 
and SkF. 

In this study, patients with duodenal GISTs containing 
SkF experienced better overall survival than patients 
with duodenal GISTs lacking SkF (100% vs. 62.5%). All 3 
patients that died in the follow up period in this study 
suffered tumor recurrence within half a year, and their 
original tumor sizes were over 50 mm. No tumor recur- 
rence or metastasis occurred in patients in this study, 
when tumors were small and were resected completely. 
Although the current classification of GISTs is appropri- 
ately based on tumor size and number of cellular divi- 
sions counted, adding the speed of tumor growth as an 
indicator of tumor malignancy may further improve the 
current risk classification system. Miettinen et al. [7] 
detected SkF in 78 (53%) of 148 patients with duodenal 
GIST, and 70 of these cases were classified as very low or 
low malignant potential. This is similar to our results, 
however no statistical evaluation of the correlation between 
SkF and survival was performed. To our knowledge, the 
present study is the first to evaluate the association of SkF 
with prognosis in duodenal GISTs. 

The major limitation of this present study was the 
small number of patients with duodenal GISTs, although 
our study does describe 20 cases with adequate follow 
up seen in 2 institutes. The largest study on 156 cases 
with duodenal GISTs was performed at the Armed Forces 
Institute of Pathology (and the Haartman Institute of the 
University of Helsinki) between 1970 and 1996 [7]. The 
second-largest study had 22 patients [6], and the third- 
largest one had only 20 patients [8]. Thus, as a general 
trend, cases with duodenal GISTs are few in number be- 
cause the duodenum is a short organ. Duodenal GISTs in 
Japanese are able to be detected early because of the so- 
cial background of proactive medical examination, and 
this early diagnosis may facilitate research into the early 
biological characteristics of this relatively unusual tumor. 
A multicenter study on duodenal GISTs must thus shed 
further light on the biologic behavior of this tumor. 

Conclusions 

We have identified clinical and histopathological factors 
that are useful in predicting prognosis in patients with 
duodenal GISTs. In this study, 60% of the tumors were 
found incidentally. Skeinoid fibers were not recognized in 



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Page 7 of 7 



tumors from 40% of patients; all cases of post-operative 
tumor recurrence and patient death occurred in patients 
with duodenal GISTs lacking SkR 

Consent 

Written informed consent was obtained from the pa- 
tient for publication of this report and any accom- 
panying images. 

Abbreviations 

EMG: Elastica-Masson Goldner; EVG: Elastica van Gieson; GIST: Gastrointestinal 
stromal tumors; HPF: High-power fields; PAS: Periodic acid and Schiff; 
SkF: Skeinoid fiber; SMA: Smooth muscle actin. 

Competing interests 

The authors declare that they have no competing interests. 
Authors' contributions 

ST, UM, NY, and WG designed and conducted the study. ST, OY, and OK 
analyzed the data, especially pathological evaluation. HM, UH, and MK 
helped to write the manuscript. WG is the principal investigator, revised and 
edited the manuscript. All authors approved the final manuscript. 

Author details 

department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, 
Bunkyo-ku, Tokyo 1 13-8603, Japan, department of Digestive Surgery, 
Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo 105-0001, Japan, 
department of Pathology, Toranomon Hospital, 2-2-2 Toranomon, 
Minato-kuTokyo 105-0001, Japan, department of Surgery, Nippon Medical 
School Hospital, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan, 
department of Pathology, Yokohama City University Graduate School of 
Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. 



10. Min KW: Small intestinal stromal tumors with skeinoid fibers: 
clinicopathological, immunohistochemical, and ultrastructural 
investigations. Am J Surg Pathol 1992, 16:145-155. 

11. Miettinen M, Makhlouf H, Sobin LH, Lasota J: Gastrointestinal stromal 
tumors of the jejunum and ileum: a clinicopathologic, 
immunohistochemical, and molecular genetic study of 906 cases before 
Imatinib with long-term follow up. Am J Surg Pathol 2006, 30:477-489. 

12. Hornick JL, Fletcher CDM: The role of KIT in the management of patients 
with gastrointestinal stromal tumors. Human Pathol 2007, 38:679-687. 

13. Emory TS, Sobin LH, Lukes L, Lee DH, O'Leary TJ: Prognosis of 
gastrointestinal smooth-muscle (stromal) tumors. Am J Surg Pathol 1999, 
23:82-87. 

14. Sakurai S, Oguni S, Hironaka M, Fukayama M, Morinaga S, Saito K: Mutations 
in c-kit gene exons 9 and 13 in gastrointestinal stromal tumors among 
Japanese. Jpn J Cancer Res 2001, 92:494-498. 

15. Min KW: Skeinoid fibers: an ultrastructural marker of neurogenic spindle 
cell tumors. Ultrastruct Pathol 1991, 15:603-61 1. 

16. Tsutusumi Y, Tazawa K, Shibuya M: Type VI collagen immunoreactivity in 
skeinoid fibers in small intestinal stromal tumors. Pathol Int 1999, 
49:836-839. 

17. Agaram NP, Baren A, Arkun K, Dematteo RP, Besmer P, Antonescu CR: 
Comparative ultrastructural analysis and KIT/PDGFRA genotype in 125 
gastrointestinal stromal tumors. Ultrastruct Pathol 2006, 30:443-452. 



doi:1 0.1 1 86/1 477-781 9-1 1 -202 

Cite this article as: Saito et al:. Histopathological and clinical 
characteristics of duodenal gastrointestinal stromal tumors as predictors 
of malignancy. World Journal of Surgical Oncology 201 3 11 :202. 



Received: 19 February 2013 Accepted: 5 August 2013 
Published: 16 August 2013 



References 



Connolly EM, Gaffney E, Reynolds JV: Gastrointestinal stromal tumors. Br J 

Surg 2003, 90:1178-1186. 

Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM: Gastrointestinal 
pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show 
phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol 
1998, 152:1259-1269. 

Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, 

Hanada M, Kurata A, Takeda M, Muhammad Tunio G, Matsuzawa Y, Kanakura Y, 

Shinomura Y, Kitamura Y: Gain-of-function mutations of c-kit in human 

gastrointestinal stromal tumors. Science 1998, 279:577-580. 

Miettinen M, Lasota J: Gastrointestinal stromal tumors: definition, clinical, 

histological, immunohistochemical, and molecular genetic features and 

differential diagnosis. Virchows Arch 2001, 438:1-12. 

Pidhorecky I, Cheney RT, Kraybill WG, Gibbs JF: Gastrointestinal stromal 

tumors: current diagnosis, biologic behavior, and management. Ann Surg 

Oncol 2007, 95:267-269. 

Goldblum JR, Appelman HD: Stromal tumors of the duodenum: a 
histologic and immunohistochemical study of 20 cases. Am J Surg Pathol 
1995, 19:71-80. 

Miettinen M, Kopczynski J, Makhlouf HR, Sarlomo-Rikala M, Gyorffy H, Burke A, 
Sobin LH, Lasota J: Gastrointestinal stromal tumors, intramural leiomyomas, 
and leiomyosarcomas in the duodenum: a clinicopathologic, 
immunohistochemical, and molecular genetic study of 167 cases. Am J Surg 
Pathol 2003, 27:625-641. 

Winfield RD, Hochwald SN, Vogel SB, Hemming AW, Liu C, Cance WG, 
Grobmyer SR: Presentation and management of gastrointestinal stromal 
tumors of the duodenum. Am Surg 2006, 72:719-723. 
Goh BK, Chow PK, Kesavan S, Yap WM, Wong WK: Outcome after surgical 
treatment of suspected gastrointestinal stromal tumors involving the 
duodenum: is limited resection appropriate? J Surg Oncol 2008, 97:388-391. 



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